Processes and intermediates for preparing 16alpha-methyl corticoids



United States Patent 3,231,568 PROCESSES AND HNTERMEDIATES FOR PREPARINGMot-METHYL CORTHCOIDS Percy L. Julian, Oak Park, and Joe M. Hill,Chicago, IlL,

assignors, by mesne assignments, to Smith Kline &

French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania NoDrawing. Filed Feb. 26, 1964, Ser. No. 347,399

12 Claims. (Cl. 260-23955) This invention relates to new processes andintermediates for the preparation of 16u-methyl steroids having apregnane nucleus. The end products prepared by this invention haveutility as corticoid steroids and many are commercially available fromexample for treating arthritis, as anti-inflammatory agents,progestationa-l agents, etc.

Reichsteins Compound S (cortexolone) is a wellknown intermediate forpreparing hydrocortisone and prednisolone by microbiological oxidationon a commercial scale. Compound S is the subject of our copendingapplication Serial No. 286,959, filed June 11, 1963. Prior to thedevelopment of this chemical process for preparing Compound S,-pregnene-3fi,17a,21-triol-20-one 3,2l-diacetate (diac) and5-pregnene-3B,17u-2l-triol-one 21-acetate (monac) and prior to theprocess and intermediates of this invention, '16a-methyl derivatives ofCompound S,

A commercially useful process for preparing 3,231,568 Patented Jan. 25,1966 ice diac or monac were very expensive and not readily available ona commercial scale.

In our US. Patent No. 3,030,389 We disclosed a' useful commercial methodof preparing 16a-methyl cortisone or hydrocortisone as Well as l6-methylCompound S using a 5,6-dichloro protective group. The preparation of thestarting material in that process, 5,6-dichloro-16-pregnen- -01-20-oueis achieved in only about yield thereby losing a substantial amount ofraw material at the outset of the process.

A substantial advantage of the present invention isthat the major partof this overall process for preparing 16ozmethyl corticoids is concernedwith relatively inexpensive intermediates having a methylene group at Crather than a hydroxymethylene or keto group. Perhaps more important isthe fact that the method of this invention afl'ordsl6-methy1-l7u-hydroxypregnenolones on a relatively ineX- pensive basis.

The nub of this invention is the protection of the A, B ring structureby a 6,8-alkoxy-3,5-cyclo or i-system while the 16-methyl-17-hydroxysystem is inserted. It is surprising that this protective system isstable under reaction conditions successful in forming the16-methyl-17-hydroxy system. It will be apparent that 6-alkoxy groupsother than methoxy can be used such as ethoxy or pro- 1 poxy groups,however the cheapest and most commercially practical protective group isthat derived from methanol, methoxy, in the fi-configuration.

i w E J=o (l3OMgX -0A0 CH. (\l/ i I CHaMgX AcCl [Ox.] \/y \/\I OCHa OOH:00113 (I) (II) (III) (IJHQ C-OAe CH3 CH3 ---01-1 ---OE T0113 Iona Ton3 ei a T on n HO n I 0on3 OCH:

(IV) (V) (VI) (llHgBr C|H2X CHzOAO 3:0 1:0 (3:0

H "-011 --011 V T0113 Tons CH3 I I i NaI H0 KOAc [Ox.]

VII (VIII) [X=Br] (X) CH2OA0 FQIJ lfia-methyl Compound S acetate (XIV)The starting material for the processes of this inven tion is, thereadily available 6-methoxy-3,5-cyclo-16-pregnen-20-one (I) [P. L.Julian et al., J. Am. Chem. Soc., 72, 368 (195 The cyclopregnen (I) isreacted under standard Grignard conditions with a methyl magnesiumhalide such as the bromide, iodide or chloride to add the Grignardreagent 1,4 across the 20-keto-A system producing. thereby thel6amethyl-20-Grignard adduct (II). While the reaction conditions of thisstep can vary widely we have found it acceptable to run the reaction inthe presence of cuprous chloride in the usual non-polar organic Grignardsolvents such as benzene, ether, tetrahydrofuran or mixtures thereof atmoderate temperatures, i .e.,' from about 050 C. Tetrahydrofuran or itsmixtures with benzene are the preferred solvent systems- Alternativelyother Grignard reagents or equivalent organo-metallic agents can beused, such as the ethyl or benzyl Grignards.

The Grignard adduct (.11) is preferably not isolated but is used at oncein the mother liquors for reaction with acetyl chloride under mildconditions such as in a suitable nonpolar organic solvent attemperatures around room temperature to form the acetyl derivative ofthe 17,20 enol (III). Other acyl halides or anhydrides can obviously beused such as those derived from carboxylic acids of a maximum of 10carbons however acetyl chloride is the most feasible commercialacylating agent.

The enol acetate (III) is then oxidized at 17,20 to formthe17,20-epoxide. The reaction step is carried out withthe usual oxidizingagents known to the art for forming oxido or epoxy derivativesespecially the preferred per acids, such as per-acetic acid,per-phthalic or per-benzoic acid preferably in a buffered system. Thereaction medium we have found most useful is sodium acetate-acetic acidin chloroform at temperatures of about room temperature or less.Per-acetic acid is the most suitable commercial oxidizing agent.

The 17,20-epoxide (IV) is thenhydrolyzed under,

I 16a-methylmonac alkaline conditions to give 6-methoxy-l6a-methyl17ochydroxy-3,5-cyclopregnan-20-one (V) an important new intermediate.The hydrolysis is usually carried out using sodium hydroxide in aqueousmethanolic or ethanolic solution at ambient temperature. novel, usefulintermediates and are an important aspect of this invention.

The cyclopregnanolone (V) is rearranged under acid conditions such aswith sulfuric acid in aqueou dioxane at reflux temperature to forml6ot-methyl-3 3,l7 dihydroxy-A -pregnen-20-one (VI) [Batres et al., J.Org. Chem, 26, 871 (1961); British Patent No. 909,614]. Alternative acidconditions for this reaction are p-toluenesulfonic acid or sulfuric acidin dioxane or acetic acid.

On using-acid in acetic acid the 3-acetate is obtained' which can beoptionally hydrolyzed with alcoholic alkali under mild conditions'asknown to the art.

The 16u-methylpregnenolone (VI) is then tribrominated and converted tothe 16e-methylmonac by the meth- Compounds IIV areods disclosed andclaimed in our copending application Serial No. 286,959. Briefly VI isbrominated with 3 .ucts.

with hydrogen chloride gas. After cooling to about 10 C. alkali, such assodium bicarbonate, is added to separate the tribromide, predominantlythe Sewn-isomer, with cooling, usually about 05 'C; The resultingproduct is therefore 5a,6,8,21tribroino 3,17-dihydroxy-l6a methylpregnan-ZO-one which .reacts smoothly in thenext step. Preferably the5a,6,B-dibromo intermediate (VII); is separated and used as thesubstantially pure crystalline product. The cis and 513,6oz-t121I1Sisomers may be isolated and recycled by debromination of the motherliquors to the pregnenolone starting material using chromous chloride(as in U.S. Patent No. 2,374,683) or zinc-acid.

The important 5a,6,8,2l-tribr0mo intermediate is then reacted with aslight excess over two molar equivalents of sodium or potassium iodidein acetone-methanol in the presence of an alkali metal salt such aspotassium acetate at room temperature then at reflux to givethe5,6-dihydro compound then the desired 16a-methyl-3,17,2 1-trihydroxy-A-pregnen-20-one-21-acetate (X, methylmonac, see Batres et al., above).Preferably the 21- halo-3B,17 x-dihydroxy-16ot-methyl-A -pregnan 20 one(VIII and IX) which in practice is a mixture of the 21- iodo and21-bromo congeners is reacted without isolation in the reaction mixturewith the acetate reagent.

The reactions (I X) are all high yield reactions carried out undersimple conditions. The outlined intermediates may each be isolated ifdesired but for the highest yields on a commercial scale no isolation orpurifications are necessary after I until V is isolated with thereactions through III taking place in the same kettle. Also reactions(III- X) take place in the same kettle Without isolation.

Compound X (16a-methy1monac) is converted into 16a-methyl-4-pregnene-11a,17ot,21-t1i01-3,20 dione (160cmethylhydrocortisone) in several ways,for example by oxidation by chemical methods such as the Jones oxidationor by oxidative fermentation as per U.S. Patent No. 3,030,278 to16a-methyl Compound S followed by stepwise fermentation of 16a-methylCompound S to the hydrocortisone and prednisolone congeners or by directfermentation of the 16a-methylmonac to these end prod- Reference may behad to U.S. Patents No. 2,985,- 563 and No. 3,030,278 or British PatentNo. 909,614.

The oxidation of 16a-methylmonac (X) to l6oc-methyl Compound S using themodified Jones oxidation was found to proceed in very high "yields.Presumably this reaction goes favorably because of the protection ofposition 17 by the adjacent methyl substituent blocking this center fromthe troublesome D-homoannulation side reaction.

The 6-methoxy-3,5-cyclo system for protecting A, B configuration canalso be used for preparing the 16;?-

' methylmonac and Compound S congeners via the reaction of diazomethaneon 6-methoxy-3,5-cyclo-16-pregnen- 20-one to insert the 16/3-methylgroup followed by insertion of the 17u-hydroxy group by the classicalGallagher procedure.

The following examples are designed to illustrated this invention tothose skilled in the art. Variations of this invention will be apparentto those reading this disclosure. Such variations may be in the reactionconditions or in the structures of the steroids themselves such ashaving inert substituents at nonreactive positions in the startingmaterials. Those variations obvious to those skilled in the art areconsidered within the ambit of this invention.

Example 1 A solution of 1 part of 3,5-cyclo-6-rnethoxy-16-pregnen-20-onein 7 parts of benzene is distilled to remove 2 parts then cooled. Fiveparts of tetrahydrofuran is mixed with 0.05 part of cuprous chloridewith vigorous stirring to this mixture at 10 C. Methyl magnesium bromide (1.78 part) is added keeping the temperature at about 10-20 C. Thesteroid containing benzene solution is added at 10 C. keeping thetemperature at 10- 20 C. The reaction mixture is stirred for two hoursat room temperature to give the Grignard adduct.

The reaction mixture containing the Grignard product is cooled to 10 C.and 0.41 part of freshly distilled acetyl chloride in 1 part benzeneadded to keep the temperature 'at 1020 C. After stirring at roomtemperature for one hour a solution of 0.6 part of ammoni- 11m chloridein 6 parts of water is added with cooling. After stir-ring and filteringthe mixture, the aqueous layer is separated, back extracting withbenzene. The separated main solution is washed twice with saturatedammonium chloride solution. A trace of pyridine is added to the benzeneextracts which are concentrated in vacuo to give a syrup residue,3,5-cyclo-6-methoxyl6a-methyl-20-acetoxy-A -pregnene. Methyl magnesiumchloride or methyl magnesium iodide can be substituted for methylmagnesium bromide using equimolar amounts.

One part of the residue is dissolved in 9 parts of chloroform and mixedwith 1.5 part of acetic acid at 5 C. The cooled solution is then reactedwith a cooled mixture of 2 parts of 40% per-acetic acid and 0.4 part ofanhydrous sodium acetate. The oxidation mixture is kept at less than 20C. for three hours then for 14-16 hours (overnight) at room temperaturewith stirring. The mixture is poured into water. The product is takeninto 4 parts of chloroform which is washed with sodium hydroxidesolution and water to neutrality. The organic extracts are combined andconcentrated in vacuo to a syrup, the 17,20-epoxide.

This compound is dissolved in 3.5 parts of methanol and stirred while0.18 part of 76% sodium hydroxide flakes in water is added. Aftervigorous stirring a crystalline product separates. Water and acetic acidto slight acidity is added. Cooling and filtration gives 3,5-cyclo- 6methoxy-16a-methyl 17a hydroxypregnan 20' one, M.P. 165-175 C.Recrystallized from chloroform-methanol, M.P. 188-190 C.

A suspension of 1 part of this cyclopregnanolone in 7 parts of dioxaneis heated to about 85-90 C. to dissolve the compound. A mixture of 0.75part Water and 0.05 part sulfuric acid is added. The mixture is heatedat reflux for about one hour while 2 parts distillate are removed. Thereaction mixture is diluted with water, cooled and filtered. Theseparated product is washed with water, slurried in hot methanol anddried to give 160: methyl 35,1704 dihydroxy A pregnen 20 one, M.P.245250 C.

A mixture of 1 part of the 16-methylpregnenolone, 7 parts of methylenechloride and 0.05 part of pyridine at about 8 C. is reacted with 0.5part bromine in 0.5 part methylene chloride. After brief stirring themixture is warmed to 3538 C. when 0.2 part of methanol and some of 0.48part of bromine is added. Hydrogen chloride gas is bubbled through thereaction mixture until bromination at C starts then add the rest of thebromine. After brief stirring the mixture is cooled to about 10 C. when0.365 part of sodium bicarbonate in 1 part of water is added cautiously.The tribromide separates while stirring at 5 C. for one hour and isseparated by filtration and Washed with water to givea,6fi,21-tribromo-3,17-dihydroxy-l6a-methyl-pregnan-20-one.

The separated 5a,6,8-trans tribromide (1 part) in 4 parts acetone with0.1 part potassium acetate is stirred while 0.76 part of sodium iodideis added then for one further hour at about room temperature. Acetone (6parts), potassium acetate (1.6 parts) and 0.1 part of methanol areadded. The reaction mixture is heated at reflux for three hours thenconcentrated to remove 6 parts solvent for reuse. Two parts of Water areadded and the distillation continued under vacuo to remove residualacetone. Adding water cooling and filtration gives 16a-methyl 3,17,21trihydroxy-A pregnen-20-one 21-acetate (16-methylmonac acetate), M.P.170-180 C. after slurrying. After purification by charcoal in acetonethe melting point is 180-185 C.

Example 2 The 16ot-methyl-17a-hydroxypregnenolone is recovered from thecis and 66,5a-transdibromides of the bromination step of Example 1 asfollows.

The methylene dichloride extracts and mother liquors from thebromination step of Example 1 are Washed to neutrality, mixed withmethanol and acetic acid With zinc dust at the boiling point. Afterstirring for 20-30 minutes the mixture is heated to reflux, allowed tosettle and the supernatant liquid decanted. The solution is concentratedand cooled to give l6a-methyl-l7a-hydroxypregnenolone which isrebrominated.

Example 3 One gram of 16-methylmonac is dissolved in pyridine andreacted with a molar equivalent amount of acetyl chloride at roomtemperature for several hours. The reaction mixture is quenched in Waterthen extracted with methylene chloride. Washing and concentration of theextracts give 16u-methyldiac.

Hydrolysis of l6-rnethylmonac (1 g.) using sodium bicarbonate inmethanol gives the free alcohol.

Example 4 20 kg. of 16a-methylmonac acetate from Example 1 in l. ofmethylene chloride is cooled to 5 C. Pyridine (0.8 l.) is added followedby a solution of 9' kg. of bromine in 101. of methylene chloride.Acetone (240-1.) is added and the mixture is cooled to 0-5 C. A solutionof 7.88 kg. of chromic acid, 8 l. of water and 6.77 l. of sulfuric acidis added holding the temperature below 23 C. Stirring is then continuedbriefly.

Methylene chloride l.) and then 350 l. of Water are added to thereaction mixture. The mixture is stirred and warmed to 30 C. The organiclayer is separated, washed with water, diluted with 60 l. of methanoland 10 l. of acetic acid then debrominated with 6.5 kg. of zinc dust.The solvent is decanted from the zinc. At 30 C., 8 l. of concentratedhydrochloric acid is added. After stirring for thirty minutes, 350 l. ofwater is added. The methylene chloride layer is separated, washed with10% caustic soda then with Water to neutrality. The methylene chloridesolution is evaporated to a very thick slurry, 140 l. of acetone isadded and the mixture is concentrated. Cooling gives a high yield ofl6u-methyl Compound S acetate, M.P. 98-103 C.

Example 5 A mixture of 5 g. of 3,5-cyclo-6B-methoxy-16a-methyl-17ot-hydroxypregnan-20-one from Example 1 is dissolved in 75 ml. ofaqueous dioxane with an excess of p-toluenesulfonic acid. The mixture isheated at reflux for three hours. Dilution with Water separates thedesired 16amethyl-315',17a-dihydroxy-A -pregnan-20-one.

A mixture of 5 g. of 3,5-cyclo-6B-methoxy-16a-methyl-17a-hydroxypregnan-20-one is dissolved in acetic acid with an excessamount of sulfuric acid. The mixture is heated at reflux for a shortperiod then cooled and quenched to separate the 3-acetyl derivative ofthe 16a-methyl-17uhydroxypregnenolone. This material (1 g.) is heated atrefluxbrieflyin aqueous methanolic sodium carbonate to give the desired16u-methyl-17u-hydroxypregnen0lone upon concentration and quenching inwater. What is claimed is:

1. The method of preparing 16ot-111EthYl-3B,1704,21-151ihydrXy-A-pregnen--one 21-acetate comprising reacting3,5-cyclo-6B-Inethoxy-16-pregnen-20-one with methyl magnesium halide toform the 16a-met-hyl-20 Grignard adduct, reacting said adduct withacetyl chloride to form V 20-acetoxy 3,5 cyclo-6/8-methoxy-16a-methyl-Apregnene, reacting said 20-acetoxy-3,S-cyclo-Gfl-methoxy- 1Ga-methyI-A-pregnene with per-acetic acid to form 20-acetoxy 3,5-cyclo 17,20 epoxy65 methoxy-16amethylpregnane, hydrolyzing said 20acetoxy-3,5-cyclo-17,20-epoxy-6/3-methoxy-16a-methylpregnane under alkaline conditions toform 3,5 cyclo 17oz hydroxy 6,8- methoxy-16a-methylpregnan-20-one,rearranging said 3,5- cyclo-17a-hydroxy 6,8-methoxy16a-methylpregnan-20- one under acid conditions to form17a-hydroxy-16ocmethylpregnenolone, reacting said methylpregnenolonewith about two moles of bromine to form 3/3,17a-dihydroxy-16a-methyl-5a,6fi,21-tribromo pregnan-ZO-one, reacting saidFiflyl'loc-dihYdDOXY-16otmethyl-5a,6fi,2l-tribromopregnan-ZO-one withfrom about 2-3 moles of an alkali metal iodide to form3B,17u-dihydroxy-2 l-halo-l6a-methyl-A -pregnen-ZO-one and reacting said3,8,17a-dihyd-roxy-2l-halo-l6a-methyl-A -pregnen-20-one with an alkalimetal acetate to form 160:- methyl 3,8,170:,21-trihydroxy-A-pregnen-2O-one 21-acetate.

2. The method of claim 1 characterized in that said 36,1711 dihydroxy16a methyl 5a,6fi,21 tribromopregnan-ZO-one is separated insubstantially pure form from the bromination reaction and used in thenext step of the reaction.

3. The method of claim 1 characterized in that said 3fl,17oc dihydroxy21 halo 16a rnethyl-A -pregnen 20-one is not isolated but is reacted inthe reaction mixture substantially immediately with potassium acetate.

4. The method of preparing 16a-methyl-4-pregnen 17a,21-diol-3,20-dione21-acetate comprising reacting 3,5 cyclo-6fi-methoxyel6-pregnen-20-onewith methyl magnesium halide to form the 16oc-methyl-20 Grignar'dadduct, reacting said adduct with 'acetyl chloride to form20-acetoxy-3,5-cyclo-6B-methoxy-16u-methyl-A -pregnene, reacting said20-acetoXy-3,5-cyclo-6 8-methoxy-Mia-methyl- A -pregnene with per-aceticacid to form 20-acetoxy- 3,5 -cyclo- 1 7,20-6p0xy-6fl-methoxy16a-methylpregnane, hydrolyzing said 20 acetoxy-3,5-cyclo-17,20-epoXy-6B- methoxy-16a-methylpregnane under alkaline conditionsto form 3,5-cyolo-17a-hydroxy-6/3-mcthoxy-16u-methylpregnan-ZO-one,rearranging said 3,S-cyclo-lh-hydroxy-Gfimethoxy-16umethylpregnan-20-one under acid conditions to form17u-hydroxy-16u-methylpregnenolone, reacting said17u-hydroxy-16u-methylpregnenolone with about two moles of bromine toseparate essentially crystalline 3 3,17a-dihydroxy-16oz-methy1 5a,6B,21-tribromopregnan- 20- one in the presence of sodium bicarbonate,reacting said 3fl,l7a-dihydroxy 16a-methy15a,6fi,21-tribromopregnan-ZO-one with from about 2-3 moles of an alkalimetal iodide to. form 3p,-17u-dihydroxy-21-halo-16amethyl-A-pregnen-ZO-one, reacting said 3,8,17a-dihy- 8 droxy-Zl-halo16u-methyl-A -pregnen-ZO-one in its reac-' tion mixture with potassiumacetate to form 16u-methyl- 3,8,17oc,2I-trihydroxy-M-pregnen-20-one'2-1-acetate I and oxidizing said 16u-methy1-3,8 ,1 7a,2l-trihydroxy-A-pregnen-ZO-one ZI-acetate.

5. A compound having the formula:

in which R is a member selected from the group consist? ing of acetyl,MgCl, MgBr and MgI.

6. la-methyl 20-acetoxy-6-methoxy- 3,5-cyclo-A pregnene.

7. ZO-acetoxy 3,5-cyclo 17,20-ep0xy-6-methoxy-16amethylpregnane.

8. 3,5 cyclo-6-methoxy- 16a methyl 17oz hydroxypregnan-ZO-one.

9. The method of preparing 17a-hydroxy-16u-methyl pregnenolonecomprising reacting 3,5-cyclo-6fi-methoxy- 16-pregnen-20-one with methylmagnesium halide to form the 16u-methyl-20-Grignard adduct, reactingsaid adduct with acetyl chloride to form20-acetoxy-3,5-cyclo-6fimethoxy-l6a-met-hyl-A -pregnene, reacting said20- acetoxy-3,5-cyclo-6fl-methoxy-16a-methyl-A -pregnene with per-aceticacid to form 20-acetoxy-3,5-cyclo-17,20-epoxy-Gfl-methoxy-l6m-methylpregnane, hydrolyzing said 20-acetoxy-35-cyclo-17,20-epoxy-6 8-methoxy-l6amethylpregnane under alkalineconditions to form 3,5-cyclo-l7ahydroxy-68-methoxy-16ot-methylpregnan-20-one and rearranging said 3,5-cyclo17a-hydroxy GB-methoxy-16amethylpregnan-ZO-one under acid conditions; e10. The method of claim 9 characterized in that said 3,5-cyclo17a-hydroxy 6,6-meth0xy 16a-methylpreg1 nan-ZO-one is rearranged underacid conditions in the presence of p-toluene'sulfonic acid in aqueousdioxane.

11. The method of claim 9 characterized in that said3,5-cyclo-l7u-hydroxy 6B-methoxy-16nt-methylpregnam 20-one is rearrangedusing a'member selected,.from the group consisting of sulfuric acid andp-toluenesulfonic acid in acetic acid to give the B-acetate derivativeof methyl-17a-hydroxypregnenolone and hydrolyzing said 35 acetatederivative with alcoholic alkali.

12. In the method of preparing '16-methyl3 8,17x dihydroxy-ZO-keto-A6-pregnene, the modification comprising protecting the 3,8-hydroxy-Asystem of the A, B ring of the pregnane nucleus by forming a3,5-cyclo-6flmethoxy system.

LEWIS GOTIS; Primary Examiner.

1. THE METHOD OF PREPARING 16A-METHYL-3B,17A,21-TRIHYDROXY-$-PREGNEN-20-ONE 21-ACETATE COMRISING REACTING3,5-CYCLO-6B-METHOXY-16-PREGNEN-20-ONE WITH METHYL MAGNESIUM HALIDE TOFORM THE 16A-METHYL-20 GRIGNARD ADDUCT, RACTING SAID ADDUCT WITH ACETYLCHLORIDE TO FORM20-ACETOXY-3,5-CYCLO-6B-METHOXY-16A-METHYL-$17,20-PREGNENE, REACTINGSAID 20-ACETOXY-3,5-CYCLO-6B-METHOXY16A-METHYL-$17,20-PREGNENE WITHPER-ACETIC ACID TO FORM20-ACETOXY-3,5-CYCLO-17,20-EPOXY-6B-METHOXY-16AMETHYLPREGNANE,HYDROLYZING SAID20-ACETOXY-3,5-CYCLO17,20-EPOXY-6B-METHOXY-16A-METHYLPREGNANE UNDERALKALINE CONDITIONS TO FORM3,5-CYCLO-17A-HYDROXY-6BMETHOXY-16A-METHYLPREGNAN-20-ONE, REARRANGINGSAID 3,5CYCLO-17A-HYDROXY-6B-METHOXY-16A-METHYLPREGNAN-20ONE UNDER ACIDCONDITIONS TO FORM 17A-HYDROXY-16AMETHYLPREGNENOLONE, REACTING SAID17A-HYDROXY-16AMETHYLPREGNENOLONE WITH ABOUT TWO MOLES OF BROMINE TOFORM 3B,17A-DIHYDROXY-16A-METHYL-5A,6B,21-TRIBROMOPREGNAN-20-ONE,REACTING SAID 3B,17A-DIHYDROXY-16AMETHYL-5A,6B,21-TRIBROMOPREGNAN-20-ONEWITH FROM ABOUT 2-3 MOLES OF AN ALKALI METAL IODIDE T FORM3B,17A-DIHYDROXY-21-HALO-16A-METHYL-$5,6-PREGNEN-20-ONE AND REACTINGSAID 3B,17A-DIHYDROXY-21-HALO-16A-METHYL-$5,6-PREGNEN-20-ONE WITH ANALKALI METAL ACETATE TO FORM 16AMETHYL-3B,17A,21-TRIGHYDROXY-$5-PREGNEN-20-ONE 21 ACETATE.